The gene for 5-HT1B serotonin receptors has been linked to alcoholism in humans but there is scant evidence for how these receptors modulate ethanol's reinforcing effects. Since 5-HT1B receptors are expressed in different groups of neurons throughout the brain, they must be studied using techniques that have anatomical and pharmacological specificity. For example, it is hypothesized that the 5-HT1B recaptors in the axon terminals of medium spiny neurons that project from nucleus accumbens shell (NAcc) to ventral tegmental area modulate drug reward by inhibiting GABA release, thereby disinhibiting dopaminergic activity. To investigate this idea, it is necessary to examine.just these 5-HT1B receptors and not those in other neurons that regulate other aspects of behavior. Toward!this aim, we will use targeted manipulation of 5-HT-iBexpression in these NAcc neurons. We will examine this hypothesis by measuring changes in ethanol consumption after manipulating the level of 5-HT1B expression in the NAcc. In Specific Aim 1, we plan to increase 5-HT1B expression using virally-mediated gene transfer and measure the effect on the initiation and maintenance of alcohol drinking behavior. In Specific Aim 2, we will knockdown expression of 5-HT1B receptors in NAcc shell using RNA interference (RNAi) and measure these same behaviors. Thus, we will use novel molecular techniques to manipulate 5-HT1B expression in a discrete group of neurons and measure the resulting changes in free choice ethanol consumption to evaluate how this receptor regulates reward mechanisms in the brain. [unreadable] [unreadable] [unreadable]